Design, synthesis and biological characterization of selective LIMK inhibitors

Boland, Sandro; Bourin, Arnaud; Alen, Jo; Geraets, Jacques; Schroeders, Pieter; Castermans, Karolien; Kindt, Nele; Boumans, Nicki; Panitti, Laura; Vanormelingen, Jessica; Fransen, Silke; Velde, Sarah Van de; Defert, Olivier

doi:10.1016/j.bmcl.2015.07.009

Cited by 23 publications

(20 citation statements)

References 22 publications

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“…Whether LIMK could also represent a potential therapeutic target in the treatment of VWD-type 2B was tested in our study. LIMK inhibitors are already under consideration for several indications (43), such as cancer (44), elevated intraocular pressure (45), pulmonary hypertension (46), and human immunodeficiency virus type 1 (HIV-1) (47). Our results ( Figure 9) show indeed that targeting LIMK restores platelet counts in 2B mice.…”

Section: V1316m (2b) Megakaryocytes (Mks)mentioning

confidence: 99%

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

et al. 2016

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Section: V1316m (2b) Megakaryocytes (Mks)mentioning

confidence: 99%

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

et al. 2016

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“…To determine treatment effects of LIMK2 inhibitor (LIMK2i) on CNCI-induced corporal fibrosis and ED, sixty 11-week-old male Sprague Dawley rats, weighing 300–350 g, were categorized into five equal experimental groups ( n = 12 each): sham surgery, bilateral CNCI, and bilateral CNCI treated with intraperitoneal injection of low-dose (2.5 mg kg −1 [body weight] bwt), medium-dose (5.0 mg kg −1 bwt), and high-dose (10.0 mg kg −1 bwt) LIMK2i (LX-7101, Cellagen Technology, San Diego, CA, USA), respectively. 15 16 The low-dose (L), medium-dose (M), and high-dose (H) LIMK2i groups were treated with once-daily intraperitoneal injections of LIMK2i for 1 week beginning on the day following CNCI. The sham (S) and crush injury (I) groups were treated with intraperitoneal administration of vehicle only (saline).…”

Section: Methodsmentioning

confidence: 99%

Role of inhibiting LIM-kinase2 in improving erectile function through suppression of corporal fibrosis in a rat model of cavernous nerve injury

et al. 2018

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We evaluated whether LIM-kinase 2 inhibitor (LIMK2i) could improve erectile function by suppressing corporal fibrosis through the normalization of the Rho-associated coiled-coil protein kinase 1 (ROCK1)/LIMK2/Cofilin pathway in a rat model of cavernous nerve crush injury (CNCI). Sixty 11-week-old male Sprague-Dawley rats were divided equally into five groups: sham surgery (S), CNCI (I), and CNCI treated with low-dose (L), medium-dose (M), and high-dose (H) LIMK2i. The L, M, and H groups were treated with a daily intraperitoneal injection of LIMK2i (2.5, 5.0, and 10.0 mg kg−1 body weight, respectively) for 1 week after surgery. The erectile response was assessed using electrostimulation at 1 week, postoperatively. Penile tissues were processed for Masson's trichrome staining, double immunofluorescence, and Western blot assay. Erectile responses in the H group improved compared with the I group, while the M group showed only partial improvement. A significantly decreased smooth muscle/collagen ratio and an increased content of fibroblasts positive for phospho-LIMK2 were noted in the I group. The M and H groups revealed significant improvements in histological alterations and the dysregulated LIMK2/Cofilin pathway, except for LIMK2 phosphorylation in the M group. The inhibition of LIMK2 did not affect the ROCK1 protein expression. The content of fibroblasts positive for phospho-LIMK2 in the H group returned to the level found in the S group, whereas it did not in the M group. However, the L group did not exhibit such improvements. Our data suggest that the inhibition of LIMK2, particularly with administration of 10.0 mg kg−1 body weight LIMK2i, can improve corporal fibrosis and erectile function by normalizing the LIMK2/Cofilin pathway.

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“…From the heat maps, we could clearly observe that the highly attentive atoms matched with the structure-activity relationship reported in the literature. For example, the 2-aminothiazole moiety of CHEMBL2070501, the pyrrolopyrimidine scaffold, dimethylamino and ester chain of CHEMBL3613609 played major impact on the IC50 values for Limk1 53,54 , and in CHEMBL2332093, the pyrazole group, the urea carbonyl, the hydroxyethyl group formed H-bonds interaction and the benzyl moiety formed hydrophobic interactions with ROCK2, all this were responsible for its high potency and selectivity 55 . These observations demonstrated that the 3DGCN had indeed successfully extracted relevant features including 3D molecular information by learning from a specific task, even though it had not been taught or given the information of functional groups.…”

Section: Performance Evaluation Of 3dgcn On Limk1 and Rock2 Datasetsmentioning

confidence: 99%

Combining Molecular Docking and Graph Convolutional Network to Discover Potential Selective Limk1 Inhibitors

Zhong¹,

Zhao²,

Chen³

2021

Preprint

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The LIM kinase 1 (Limk1) has been demonstrated to be considered a therapeutic target and selective inhibitors of Limk1 rather Rho-associated kinase 2 (ROCK2) are considered of interest for the treatment of several indications such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and cancer migration/invasion. Here, we utilized molecular docking to screen potential compounds of Limk1 from Traditional Chinese Medicine (TCM) database. Meanwhile, we performed a three-dimensional graph convolutional network (3DGCN), based on 3D molecular graph, to predict the inhibitory activity of Limk1 and ROCK2. Compared with the baseline models (RF, GCN and Weave), the 3DGCN achieved higher accuracy and the averaged RMSE values on test sets for Limk1 and ROCK2 were 0.721 and 0.852 respectively. In 3DGCN, above 80% of the test-set molecules from both two datasets were predicted within absolute error of 1.0 and the feature visualization suggested that it could automatically learn relevant structure features including 3D molecular information from a specific task for prediction. Furthermore, molecular dynamics (MD) simulations within 100 ns were employed to verify the stability of ligand-protein complexes and reveal the binding modes of the potential selective lead compounds of Limk1. Finally, integrating docking results, the predicted values by the 3DGCN and the MD analysis, we found that 7549, 2007_15649 and 3519 might be the potential and selective inhibitors for Limk1 receptor rather than ROCK2.

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Design, synthesis and biological characterization of selective LIMK inhibitors

Cited by 23 publications

References 22 publications

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B

Role of inhibiting LIM-kinase2 in improving erectile function through suppression of corporal fibrosis in a rat model of cavernous nerve injury

Combining Molecular Docking and Graph Convolutional Network to Discover Potential Selective Limk1 Inhibitors

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